The present invention relates to compounds of Formula I which are useful as Urokinase (uPA).
One of the most active areas in cancer research is the field of proteolytic enzymes and their role in the spread of cancer. One such class of protease, that plays a significant role in the progression of cancer, are the serine proteases, in particular Urokinase-type plasminogen activator (uPA). Inhibitors of uPA have been postulated to be of therapeutic value in treating cancer.
Disclosed in U.S. Pat. No. 5,576,343 are aromatic amidine derivatives and salts thereof. These compounds comprise amidino substituted indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazoyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl groups, attached to a substituted phenyl ring by an alkylene group having from 1 to 4 carbon atoms.
In spite of various efforts, desirable treatment for cancer remains elusive. One of the hurdles is finding an appropriate compound which has the therapeutic attributes necessary to be an effective drug. These attributes are significantly affected by the pKa values of compounds, solubility of the compounds, bio-availability of the compound, average residence time of the compound in the blood stream, etc. There is thus a need for new compounds that will be effective in inhibiting uPA. We have surprisingly found that compounds of the present invention are selective uPA inhibitors with desirable pKa values, average residence time and enhanced bioavailability.
The present invention provides compounds of Formula I: 
its prodrug forms or pharmaceutically acceptable salts thereof, wherein
R1 represents OH;
R2 represents phenyl or nitrophenyl;
R3 represents H;
R4 represents (CH2)0-2-tetrazolyl or (CH2)0-2-triazolyl;
R5 represents H;
R6 represents H;
R7 represents amino, amidino or guanidino;
R8 represents halogen; and
R9 represents H.
The present invention in a preferred embodiment provides a compound of Formula I selected from:
6-Chloro-2-[2-hydroxy-5-(1H-tetrazol-5-yl)-biphenyl-3-yl]-1H-indole-5-carboxamidine;
6-Fluoro-2-[2-hydroxy-5-(1H-tetrazol-5-yl)-biphenyl-3-yl]-1H-indole-5-carboxamidine;
6-Fluoro-2-[2-hydroxy-3xe2x80x2-nitro-5-(1H-tetrazol-5-yl)-biphenyl-3-yl]-1H-indole-5-carboxamidine;
6-Chloro-2-[2-hydroxy-3xe2x80x2-nitro-5-(1H-tetrazol-5-yl)-biphenyl-3-yl]-1H-indole-5-carboxamidine;
6-Chloro-2-[2-hydroxy-3xe2x80x2-nitro-5-(3H-[1,2,3]triazol-4-yl)-biphenyl-3-yl]-1H-indole-5-carboxamidine;
6-Chloro-2-[2-hydroxy-5-(3H-[1,2,3]triazol-4-yl)-biphenyl-3-yl]-1H-indole-5-carboxamidine;
6-Fluoro-2-[2-hydroxy-5-(3H-[1,2,3]triazol-4-yl)-biphenyl-3-yl]-1H-indole-5-carboxamidine; and
6-Fluoro-2-[2-hydroxy-3xe2x80x2-nitro-5-(3H-[1,2,3]triazol-4-yl)-biphenyl-3-yl]-1H-indole-5-carboxamidine.
Another preferred embodiment provides a compound of Formula I 
its prodrug forms or pharmaceutically acceptable salts of, wherein
R1 represents OH;
R2 represents phenyl;
R3 represents H;
R4 represents tetrazolyl or triazolyl;
R5 represents H;
R6 represents H;
R7 represents amino, guanidino or amidino;
R8 represents halogen; and
R9 represents H.
Provided in yet another preferred embodiment is a compound of Formula I:
wherein
R1 represents OH;
R2 represents nitrophenyl;
R3 represents H;
R4 represents tetrazolyl or triazolyl;
R5 represents H;
R6 represents H;
R7 represents amidino;
R8 represents halogen; and
R9 represents H.
Another aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according of Formula I, or a pharmaceutically acceptable salt thereof.
Yet another aspect of the present invention provides a method for treating or preventing a cancer related disorder, comprising administering to a patient/mammal in need thereof, a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
Synthesis
The novel compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. Described herein are some of the synthetic methods for synthesizing novel compounds of the present invention. All temperatures reported herein are in degrees Celsius (xc2x0 C.), unless indicated otherwise.
The novel compounds of Formula I can be prepared using the reactions and synthetic techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group, if necessary, used for the protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups in Organic Synthesis, Wiley and Sons, 1991). Proton NMR""s (1H NMR) were obtained using deuterated solvents such as dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or other appropriate solvents.